The major goal of this proposal is to increase our understanding of the underlying mechanism(s) involved in estrogen carcinogenesis. The production of free radical species has been postulated to be associated with several human pathological conditions, including hormonal carcinogenesis and neuronal degradation, and is also the consequence of metabolism of several xenobiotics and antineoplastic agents. The experimental approach to attain this goal is made possible by the recent successes in our laboratories in the isolation and stabilization of estrone-3, 4-quinone (3,4-EQ) and other ortho-quinones, as well as the observation that 3,4-EQ induces single strand- but not double-strand DNA breaks. Collectively, these findings present a unique opportunity to integrate the expertise of the key scientific personnel involved in these diverse areas in an effort to achieve the following specific objectives: 1. Synthesize and secure estrogen o-quinones and other important compounds having the catechol/o-quinone group in their structure. 2. Characterize the type, specificity and repair of DNA damage induced in human cells treated with o-quinones. 3. Elucidate cellular biochemical determinants mediating the metabolism of o-quinones to DNA damaging species. 4. Identify o-semiquinones and oxyradicals eliciting DNA damage in o- quinone-treated human cells using electron spin resonance spectroscopy.
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